Bladder Cancer Paradigm Expanding to Include Immunotherapy Combos, Targeted Therapies

Terence Friedlander, MD

The bladder cancer community has generated excitement with 5 monotherapy approvals for PD-1/PD-L1 inhibitors within the last year, including nivolumab (Opdivo), durvalumab (Imfinzi), avelumab (Bavencio), atezolizumab (Tecentriq), and pembrolizumab (Keytruda).

Now, ongoing clinical trials are aiming to further advance the treatment paradigm by investigating targeted agents, as well as immunotherapy-based combinations.

For example, a 2-part, first-in-human, dose-escalation/expansion study explored the fibroblast growth factor receptor (FGFR) inhibitor BGJ398 in patients with non—small cell lung cancer (NSCLC) and other solid tumors, including urothelial carcinoma, who harbored the FGFR genetic alteration. Findings showed that there were 7 partial responses, 6 confirmed, with BGJ398 doses ≥ 100 mg in patients with FGFR1-amplified squamous NSCLC and FGFR3-mutant bladder/urothelial cancer. The targeted therapy was also associated with a manageable safety profile.

Additionally, a phase I/II safety and pharmacology study is investigating the combination of atezolizumab with Bacille Calmette-Guérin (BCG) in patients with high-risk, non-muscle invasive bladder cancer (NCT02792192).

“These PD-1/PD-L1 agents are being tested across the board in bladder cancer,” said Terence Friedlander, MD. “There is a lot more to come besides PD-1. This is just the beginning; it’s not the end of the story. [There are] combinations with IDO inhibitors, adenosine A2a receptor antagonists, OX40 agonists, and CTLA-4 inhibitors—just a number of other immune partners. [There are also] combinations with chemotherapy, radiation therapy, and targeted agents.”

OncLive: Please summarize the key points of your discussion.

Friedlander, an assistant clinical professor in the Division of Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center at University of California, San Francisco, lectured on the continuous change occurring in the bladder cancer landscape during the 2017 OncLive^® State of the Science Summit^TM on Genitourinary Cancers. In an interview, he spoke about the targeted therapies emerging in the field, as well as immunotherapy combinations that are travelling through the pipeline.Friedlander: The major focus of my talk was on immunotherapy, because there has been just a number of new agents approved and there is a lot of excitement in the field right now about using these drugs. We discussed why immunotherapy might work, and 1 of the major take-home points is that bladder cancer is very mutated compared with other agents. That has to do with other exposures, including tobacco, environmental, and industrial exposures that cause a lot of damage to the bladder lining and can cause the cancer to form. That presents a lot of targets for both the immune system to see an attack and target for targeted therapy.

In terms of immune therapy, we spoke about where these drugs are approved and where an oncologist treating a patient with bladder cancer can use them in 2017. The first group that these drugs are approved in are metastatic patients who are not eligible for cisplatin, which is the mainstay of chemotherapy for these patients. While it works and there is a decent response rate, it’s not a good long-term solution. The average survival is only 1 to 1.5 years for patients who just receive chemotherapy. For patients who are ineligible for cisplatin—which is defined as poor renal function, poor performance status, neuropathy, or hearing loss—the agents atezolizumab and pembrolizumab are both approved. They are given, essentially, as monotherapy every 3 weeks.

What we are seeing that is true across the board in bladder cancer is about 20% to 25% of patients are responding to these drugs. When they respond, it’s great because they are long-term responses, in general; they tend to be durable and measured in years for most patients. The other piece is that responses happen quickly. You can do a scan and see a patient responding in as short as 6 weeks. That is exciting and encouraging; it is sort of winning the lottery with these patients because you’re getting an agent that provides long-term control of the cancer. Overall, the toxicity rates look fairly good; there is only about a 10% or 15% rate of grade 3/4 toxicity. It is sort of like a trifecta of efficacy, long-term responses, and tolerability.

We then talked about the second-line setting, and this is where the drugs have been the most well investigated—in the post-platinum setting. That could be in any setting: neoadjuvant therapy, adjuvant therapy, or for metastatic disease that has already been treated with platinum therapy. There have been 2 phase III studies performed in that setting and a bunch of phase II studies. There are 5 agents approved in that setting: pembrolizumab, atezolizumab, durvalumab, avelumab, and nivolumab. The pembrolizumab and atezolizumab data are the most robust because they are from phase III studies. The response rates and the toxicity rates were very similar to what I already said with a 20% to 25% response rate and the toxicity looks fairly good.

We did sort of drill in on the atezolizumab phase III study IMvigor211, which was presented a few months ago. It is a confusing study for a lot of folks, because the study was called negative if you read the press release. However, the way the study was designed led to that being negative. If you look at the overall survival (OS) of atezolizumab compared with chemotherapy, which is the comparator, results showed that in all comers, there was a statistically significantly benefit with atezolizumab. The curves separated as you might expect.

The way the study was designed, though, is that they were initially looking at just the PD-L1—high subset. In that group, there was not a significant difference between atezolizumab and chemotherapy—rather, it was in all comers. Therefore, if the study was designed a little differently, then that would have been a positive study. Although the study was called negative, the jury is still a little bit out. The drug clearly has activity based on a lot of data that have already been presented. In the frontline setting, pembrolizumab has a clear survival benefit. It is a level 1 recommendation.

The other agents are all in different trials and in different settings in bladder cancer. The studies of frontline immunotherapy are either as monotherapy or in combination with chemotherapy. Then, there are a number of studies earlier on, such as combinations with BCG for non-muscle invasive disease or after BCG for patients who have not had their bladders removed but maybe need cystectomy. There are adjuvant studies going on after removal of the bladder to see if we can cure people who would otherwise relapse, as well as combinations with radiation therapy.

We switched and talked about targeted therapy. I focused on 3 major developments, the first being FGFR. That is mutated or overexpressed…in about 20% of muscle invasive tumors; that might be higher in metastatic tumors. Essentially, there are antibodies being developed that inhibit the receptor. We reviewed the data that was presented from the FGFR inhibitor BGJ398, which showed some durable long-term responses. That is really exciting for targeted therapy in bladder cancer, because there has not been many studies of targeted therapy that have shown durable responses like that.

There are a number of other compounds in trials, so that is an exciting next step because it is independent of the immune system in a way; it sort of offers another opportunity for bladder cancer patients to benefit.

There was recently a phase III study presented of ramucirumab (Cyramza) and there was a modest benefit seen in the second-line setting in post-platinum metastatic patients when given together with a taxane. The benefit was modest—a 1.5-month difference in progression-free survival (PFS). Is that clinically meaningful? Thinking about the future, does that mean we will use ramucirumab in combination with chemotherapy, or should these be added to the armamentarium for adding it to a PD-1 inhibitor or to other contexts? We are going to see trials looking at that to figure out how to best use this. With bevacizumab (Avastin), there are studies we are waiting on data for.

We mentioned targeting ERBB2, which is mutated or overexpressed in bladder cancer in 10% or 15% of patients. Unfortunately, targeting it with trastuzumab (Herceptin) or lapatinib (Tykerb) in phase II/III studies has not really panned out. There hasn’t been a tremendous benefit observed, which could be due to the study design, but it may also be that it’s just not as important as a driver of bladder cancer.

In the second-line setting, how do you decide which of the 5 checkpoint inhibitors to use?

Putting that all together, it is an exciting time in bladder cancer—between immunotherapy and targeted therapies. The treatment landscape is going to change. If we come back 5 years from now, it’s going to look very different. It is a great time to be treating these patients and it is great to be able to offer so much for them. Great question. The overarching answer is we don’t really know. The cleanest data, I should say, is for pembrolizumab from the KEYNOTE-045 study because there was an OS benefit. It was clear that it was independent of PD-L1 expression, and if you look at NCCN, that’s essentially the category 1 recommendation. There is a lot of rationale still to give atezolizumab in this setting if you look at the intent-to-treat population; it was a positive study. It is just a challenge.

How often do you observe pseudoprogression with immunotherapy agents?

Whether to use the other agents—nivolumab, avelumab, or durvalumab—they are options. If a provider is very comfortable using those agents, it’s not wrong to give it. It is very reasonable to do. There are community physicians out there who are very comfortable using nivolumab, so it is very reasonable to give it in bladder cancer. If you look at the efficacy rates of these agents, they are very similar; 20% of patients respond and the toxicity rates look similar. Obviously, they haven’t been compared formally in a head-to-head comparison. In the absence of that, it’s a reasonable thing to do. I don’t proactively tell people to only give one drug, because I don’t think that’s necessarily the right way to go about this. There is about a 20% rate of pseudoprogression in bladder cancer. Knowing when to stop these drugs is a real challenge. Most of the trials allowed patients to remain on past radiographic progression. If they were clinically benefiting from the drug, my practice is to continue these agents in the absence of clear clinical deterioration, which means worsened pain, need for radiation, and in the absence of clear progression on scans where it may be multiple new growing metastases, or metastases in a critical location like in the spinal cord or the renal hilum, or the areas where I am worried that they are going to need a significant surgical or radiological intervention.

If I see progression on more than 2 consecutive scans, that is very likely true progression. That means you should think about switching therapy. The obvious challenge in bladder cancer is we don’t have a lot of [different] therapies. We have only 2 FDA-approved therapies, which are platinum and PD-1/PD-L1 agents, so I try to put patients on a study whenever I can. That should be true for all patients. The decision of when to call it for PD-1 monotherapy is challenging.

There are patients who benefit from platinum therapy. While there is so much enthusiasm and excitement for PD-1 therapy, the response rate is only about 20%. If you’re betting, I tell patients, “You would bet that you’re not going to respond to this drug.” Providers have to be honest about that and realistic about the likelihood of response. There have been cases of patients who had PD-1 treatment, didn’t respond at all and had progression, then received chemotherapy, and had very good responses. Whether that is because they were pretreated with immunotherapy and then got chemotherapy, perhaps—or, perhaps they were just destined to respond to chemotherapy.

It’s a call for better biomarkers. We can look for things like mutational burden, T-cell infiltration, effector T-cell scores, The Cancer Genome Atlas subtypes, and there are a number of other biomarkers that are deeper than PD-L1. Hopefully, that is where the field is moving—not just in bladder cancer, but across all of oncology.

Nogova L, Sequist LV, Perez Garcia JM, et al. Evaluation of BGJ398, a fibroblast growth factor receptor 1-3 kinase inhibitor, in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors: results of a global phase I, dose-escalation and dose-expansion study. J Clin Oncol. 2017;35(2):157-165. doi: 10.1200/JCO.2016.67.2048.